PROJECT SUMMARY The complexity and multifactorial nature of Alzheimer's disease (AD) pose unique challenges for mechanistic studies and developing therapies. Age is the major risk factor for AD, and imaging and biomarker data suggest that the pathophysiological processes of AD begin more than a decade before dementia is diagnosed. Apolipoprotein (apo) E4, the major genetic risk factor for AD, lowers the age of onset in a gene dose?dependent manner. In most clinical studies, apoE4 carriers account for 60?75% of AD cases, highlighting the importance of apoE4 in AD pathogenesis. Longitudinal studies show that apoE4's detrimental effect on cognition depends on age and occurs before typical signs of AD arise. A challenge in AD research is to fully understand how risk factors, including apoE4 and age-related prodromal processes, interact to contribute to AD pathophysiology. This proposal is based on intriguing preliminary findings. First, in brain hippocampal slices, intrinsic gamma oscillations are impaired in apoE4 knock-in (KI) mice at 7 months of age, indicating impaired local network function. Second, apoE4 expression disrupts mitochondrial respiration and increases production of reactive oxygen species, likely resulting in oxidative stress and neuronal ATP depletion. Third, neuronal hypometabolism self-perpetuates, causing network alterations such as hyperexcitability responsible for increased seizure susceptibility of apoE4-KI mice and rendering the brain especially vulnerable to additional stresses induced by AD-associated amyloid-beta (A?) peptide, the production of which is known to be increased under metabolic crises. In addition, recent publications from my collaborator lab show that expression of apoE4 in female mice causes age-dependent impairment of GABAergic interneurons in the hippocampus, and that this impairment is associated with reduced slow gamma activity and correlates with the severity of learning and memory deficits. Understanding the mechanisms behind age-dependent apoE4 disruption of network function and the underlying metabolic pathology will help advance the preventative strategies for people at risk for AD. This proposal aims (1) to determine the effect of aging on apoE4 disruption of hippocampal network function and its relationship with GABAergic interneuron impairment, (2) investigate cell-specific effects of aging on apoE4-induced alterations in neuronal energy metabolism and their effects on network function, and (3) determine the age-dependent effects of apoE4 on cell type-specific susceptibility to A? toxicity. The outcomes of the proposed study will shed light on primary mechanisms of apoE4-induced pathological aging and dementia, as well as on synergistic effects of apoE4 with other AD-related factors that contribute to pathogenesis of late- onset AD.